title: Inhibition of STIM1 phosphorylation underlies resveratrol-induced inhibition of store-operated calcium entry.
abstract: Resveratrol, a natural phytoalexin that shows health-promoting benefits, is an inhibitor of store-operated calcium entry (SOCE). Knowledge of the molecular mechanism underlying this inhibition is required for the proper design of therapies that include resveratrol or related stilbenoids, but remains largely unknown. To unravel this mechanism, using HEK293 cells as a model, we found that resveratrol inhibited the ERK1/2 activation triggered by Ca²⁺ store depletion. As a consequence, resveratrol inhibited STIM1 phosphorylation at residues Ser575, Ser608, and Ser621. Because this phosphorylation regulates the dissociation of STIM1 from the microtubule plus-end binding protein EB1 under store depletion conditions, resveratrol inhibited STIM1-EB1 dissociation. This inhibition had downstream effects such as inhibition of STIM1 multimerization in response to store depletion, and a significant impairment in the binding of STIM1 to ORAI1. Although additional targets for resveratrol in the molecular mechanism that governs SOCE cannot be discarded, the present results demonstrate that ERK1/2 pathway is a major target for resveratrol, and that the impairment of its activation produces a significant inhibition of SOCE.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Life Sciences, University of Extremadura, Badajoz, Spain; Department of Cell Biology, School of Life Sciences, University of Extremadura, Badajoz, Spain. Electronic address: vanessacr@unex.es.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Casas-Rua
authors.forename: Ignacio S
authors.initials: IS
authors.lastname: Alvarez
authors.forename: Eulalia
authors.initials: E
authors.lastname: Pozo-Guisado
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Martín-Romero
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D018929:Cell Culture Techniques; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D000071740:ORAI1 Protein; D010766:Phosphorylation; D011485:Protein Binding; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D000071737:Stromal Interaction Molecule 1; D014162:Transfection
chemical_list: D015220:Calcium Channels; C500985:MAPRE1 protein, human; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D013267:Stilbenes; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D000077185:Resveratrol; D002118:Calcium
keywords: Calcium signaling; ERK1/2; End-binding protein 1; Resveratrol; Resveratrol [PubChem (CID: 445154)]; STIM1; Store-operated calcium entry